Preparation method of ambroxol hydrochloride injection

Abstract

The invention discloses a preparation method of an ambroxol hydrochloride injection, which comprises the following steps: (1) adding water for injection into a liquid preparation tank, controlling the temperature of the water for injection to be 60-80 DEG C, stirring, adding a pH regulator, stirring and dissolving, adding 15g of ambroxol hydrochloride, stirring and dissolving, adding 15g of sodium chloride, stirring and dissolving, and supplementing the balance of water for injection, the pH (Potential of Hydrogen) value of the liquid medicine is 4.5 to 5.5; (2) filtering the liquid medicine by using 0.22 mu m polyether sulfone; (3) controlling the temperature of the liquid medicine to be 20-40 DEG C, filling nitrogen, and carrying out heat sealing; (4) sterilizing the sealed liquid medicine at the temperature of 115 to 125 DEG C for 10 to 20 minutes; and (5) carrying out light inspection and packaging. The preparation method of the ambroxol hydrochloride injection is simple in process, low in cost and high in safety. And the prepared ambroxol hydrochloride injection is high in bioavailability and stable in performance.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and in particular to a method for preparing ambroxol hydrochloride injection. Background Art

[0002] The common dosage forms of ambroxol hydrochloride at present include tablets, oral solutions, capsules, granules, etc. The above dosage forms have the defects of low bioavailability, large gastrointestinal side effects, high manufacturing cost, and complicated production process. In order to improve bioavailability, reduce gastrointestinal side effects, and simplify the production process while ensuring drug efficacy, the present application proposes a preparation method of ambroxol hydrochloride injection. Summary of the invention

[0003] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention aims to provide a method for preparing ambroxol hydrochloride injection, which has simple process and stable drug effect.

[0004] According to an embodiment of the present invention, the present invention provides a method for preparing ambroxol hydrochloride injection, comprising the following steps:

[0005] (1) Add 60% to 90% of the prepared amount of water for injection into a liquid preparation tank, control the temperature of the water for injection to 60° C. to 80° C., stir, add a pH adjuster, stir to dissolve, add 15 g of ambroxol hydrochloride, stir to dissolve, add 15 g of sodium chloride, stir to dissolve, add the remaining amount of the water for injection, and obtain a liquid medicine with a pH value of 4.5 to 5.5; (2) Filter the liquid medicine with 0.22 μm polyethersulfone; (3) Control the temperature of the liquid medicine to 20° C. to 40° C., fill with nitrogen, and seal by melting; (4) Sterilize the sealed liquid medicine at 115 to 125° C. for 10 to 20 minutes; (5) Perform light inspection, package, and obtain the liquid medicine.

[0006] According to the preparation method of the ambroxol hydrochloride injection of the present invention, the preparation process of the liquid medicine can be completed in the liquid preparation tank, which simplifies the liquid preparation process and procedures, reduces the cost, and improves the safety in the production process. In addition, the obtained ambroxol hydrochloride injection has high bioavailability and stable performance.

[0007] According to some embodiments of the present invention, the pH adjuster includes citric acid monohydrate and polyethylene glycol 400.

[0008] According to some embodiments of the present invention, the pH adjuster comprises an acid and a salt.

[0009] According to some embodiments of the present invention, the pH adjuster includes citric acid and anhydrous disodium hydrogen phosphate.

[0010] According to some embodiments of the present invention, the pH adjuster includes citric acid monohydrate and disodium hydrogen phosphate dihydrate.

[0011] According to some embodiments of the present invention, the liquid preparation tank is a stainless steel tank.

[0012] According to some embodiments of the present invention, the liquid preparation tank includes: a tank body; and a weighing module, wherein the weighing module is disposed at the bottom of the tank body to display the weight of the weighing portion.

[0013] According to some embodiments of the present invention, the top of the tank body is formed with: a first feeding port, a second feeding port and an exhaust hole.

[0014] According to some embodiments of the present invention, the packaging uses a brown borosilicate glass ampoule.

[0015] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Schematic diagram of the structure of a liquid dispensing tank according to a specific embodiment of the present invention.

[0017] 100: liquid preparation tank;

[0018] 1: tank body; 11: first feeding port; 12: second feeding port; 13: exhaust hole; 14: discharge port;

[0019] 2: Weighing module. DETAILED DESCRIPTION

[0020] The preparation method of the ambroxol hydrochloride injection according to the embodiment of the present invention is described in detail below.

[0021] The preparation method of ambroxol hydrochloride injection according to the present invention comprises the following steps:

[0022] (1) Add 60% to 90% of the prepared water for injection into the liquid preparation tank 100, control the temperature of the water for injection to 60° C. to 80° C., stir, add a pH adjuster, stir to dissolve, add 15 g of ambroxol hydrochloride, stir to dissolve, add 15 g of sodium chloride, stir to dissolve, add the remaining amount of water for injection, and obtain a liquid medicine with a pH value of 4.5 to 5.5; in this way, the preparation process of the liquid medicine can be completed in the liquid preparation tank 100, which simplifies the liquid preparation process and procedures, saves costs, and improves the safety of the production process.

[0023] (2) The drug solution is filtered through 0.22 μm polyethersulfone; this setting ensures the purity of the drug solution.

[0024] (3) The temperature of the drug solution is controlled at 20°C to 40°C, and nitrogen is filled and sealed. This arrangement ensures that the drug solution is stored in a nitrogen environment, reducing the risk of deterioration during storage.

[0025] (4) The sealed liquid medicine is sterilized at 115° C. to 125° C. for 10 to 20 minutes. In this way, the sterilization process ensures the sterility of the liquid medicine before packaging.

[0026] (5) After inspection and packaging, the product is ready.

[0027] According to the preparation method of ambroxol hydrochloride injection of the specific embodiment of the present invention, in a relatively open environment, the preparation process of the medicinal liquid can be completed in the liquid preparation tank 100, the process and operation of liquid preparation are simplified, the cost is saved, and the safety in the production process is improved. And the bioavailability of the obtained ambroxol hydrochloride injection is high and the performance is stable. Further, the preparation method is prepared under high temperature conditions in the production process, and the quality inspection items can still meet the requirements, which brings convenience to production. Further, the preparation method is prepared without nitrogen filling in the production process, and the quality inspection items can still meet the requirements, which brings convenience to production.

[0028] The preparation method of the present invention can ensure product quality, and no activated carbon is introduced in the production process, thereby avoiding the risk of activated carbon polluting the environment and medicines, and adsorbing medicines. In this way, a comprehensive comparison can be made from the control level of raw materials and drug packaging materials, the cleaning control level of production equipment, and the control of the production process, and multiple aspects of research can be conducted to obtain an environmentally friendly, low-cost, and quality-guaranteed preparation method for ambroxol hydrochloride injection.

[0029] According to some embodiments of the present invention, the pH regulator includes citric acid monohydrate and polyethylene glycol 400. In this way, citric acid monohydrate and polyethylene glycol 400 are used to adjust the pH value of the liquid medicine to obtain an ambroxol hydrochloride injection with a pH value of 4.5 to 5.5, and the performance of the liquid medicine is stable.

[0030] According to some embodiments of the present invention, the pH regulator includes acid and salt. In this way, the pH value of the liquid medicine is adjusted by acid and salt to obtain an ambroxol hydrochloride injection with a pH value of 4.5 to 5.5, which has stable performance.

[0031] According to some embodiments of the present invention, the pH buffer pair includes citric acid and anhydrous disodium hydrogen phosphate. In this way, anhydrous disodium hydrogen phosphate and citric acid are used as a buffer pair to adjust the pH value of the injection, thereby increasing the safety of medication. At the same time, referring to the registration status of CDE raw and excipient packages, anhydrous disodium hydrogen phosphate has been registered by multiple manufacturers, and the raw material sources are wide, which provides convenience for the selection of excipient manufacturers for enterprises.

[0032] According to some embodiments of the present invention, the pH regulator includes citric acid monohydrate and disodium hydrogen phosphate dihydrate. In this way, anhydrous disodium hydrogen phosphate and citric acid are used as a buffer pair to adjust the pH value of the injection, indicating that the preparation method of the present invention has a certain universality for pH regulators.

[0033] According to some embodiments of the present invention, the liquid preparation tank 100 is a stainless steel tank. In this configuration, the use of a stainless steel tank is safe and reliable, and has a low cost.

[0034] Combination Figure 1 According to some embodiments of the present invention, the liquid preparation tank 100 includes: a tank body 1; and a weighing module, which is arranged at the bottom of the tank body 1 to display the weight of the weighing part. In this way, the weighing module can be used to weigh the specific weight of the liquid in the liquid preparation tank 100, and the liquid can be volumetrically determined by weight. Optionally, the weighing module includes 3 or 4 submodules, and the 3 or 4 submodules are evenly dispersed at the bottom of the liquid preparation tank 100. But it is not limited to this.

[0035] According to some embodiments of the present invention, the top of the tank body 1 is formed with: a first feeding port 11, a second feeding port 12 and an exhaust hole 13. With such a configuration, liquid materials can be added through the first feeding port 11, and solid materials can be added through the second feeding port 12. At the same time, during the feeding reaction, the exhaust is exhausted through the exhaust hole 13, so that the gas generated in the liquid preparation tank 100 is discharged in time, ensuring that the liquid medicine reacts safely in the liquid preparation tank 100.

[0036] According to other embodiments of the present invention, a discharge port 14 is formed at the bottom of the tank body 1 to facilitate the discharge of the liquid feed.

[0037] According to some embodiments of the present invention, the packaging adopts brown borosilicate glass ampoule. In this way, the brown borosilicate glass ampoule packaging has good sealing performance and certain light-shielding performance.

[0038] The preparation method of the ambroxol hydrochloride injection of the present invention is described below through specific exemplary embodiments and comparative examples.

[0039] Example 1

[0040] Table 1. Prescription (2000ml)

[0041] Ambroxol Hydrochloride 15g Sodium chloride 15g Citric acid 2g Anhydrous disodium hydrogen phosphate 2.92g Nitrogen Moderate Add water for injection to 2L

[0042] Preparation method:

[0043] (1) Add 80% of the total preparation amount of water for injection into the container and control the water temperature at 70°C;

[0044] (2) Turn on stirring, add the prescribed amount of citric acid and anhydrous disodium hydrogen phosphate, stir and dissolve, add the prescribed amount of ambroxol hydrochloride, stir and dissolve, add the prescribed amount of sodium chloride, stir and dissolve, after all of them are dissolved, add water for injection to the prepared amount, and obtain a product with a pH value of 5.0;

[0045] (2) After passing the test, prepare for filling and filter the liquid through 0.22 μm polyethersulfone;

[0046] (3) Filling: Before filling, the temperature of the liquid medicine should be controlled at room temperature. Nitrogen filling and sealing should be performed;

[0047] (4) Sterilization and leak detection: sterilize in a water bath at 121°C for 15 minutes;

[0048] (5) The sterilized products that have passed the test will be inspected and packaged.

[0049] Example 2

[0050] Table 2. Prescription (2000ml)

[0051] Ambroxol Hydrochloride 15g Sodium chloride 15g Citric acid monohydrate 2g Disodium hydrogen phosphate dihydrate 3.66g Nitrogen Moderate Add water for injection to 2L

[0052] Preparation method:

[0053] (1) Add 80% of the total preparation amount of water for injection into the container, and control the water temperature at 70°C; start stirring, add the prescribed amount of citric acid monohydrate and disodium hydrogen phosphate dihydrate, stir and dissolve, add the prescribed amount of ambroxol hydrochloride, stir and dissolve, add the prescribed amount of sodium chloride, stir and dissolve. After all of them are dissolved, add water for injection to the preparation amount, so that the pH value of the product is 5.0;

[0054] (2) After passing the test, prepare for filling. Filter the liquid through 0.22 μm polyethersulfone;

[0055] (3) Filling. Before filling, control the temperature of the liquid medicine to room temperature. Perform nitrogen filling and sealing;

[0056] (4) Sterilization and leak detection: sterilize in a water bath at 121°C for 15 minutes;

[0057] (5) The sterilized products that have passed the test will be inspected and packaged.

[0058] Example 3

[0059] Table 3. Prescription (2000ml)

[0060] Ambroxol Hydrochloride 15g Sodium chloride 15g Citric acid monohydrate 0.013g Polyethylene glycol 400 13g Nitrogen Moderate Add water for injection to 2L

[0061] Preparation method:

[0062] (1) Add 80% of the total preparation amount of water for injection into the container, and control the water temperature at 70°C; start stirring, add the prescribed amount of citric acid monohydrate and polyethylene glycol 400, stir and dissolve, add the prescribed amount of ambroxol hydrochloride, stir and dissolve, add the prescribed amount of sodium chloride, stir and dissolve. After it is completely dissolved, add more water for injection to the preparation amount; make the pH value of the product 4.5;

[0063] (2) After passing the test, prepare for filling and filter the liquid through 0.22 μm polyethersulfone;

[0064] (3) Filling: Before filling, the temperature of the liquid medicine is controlled at room temperature, and nitrogen is filled and sealed;

[0065] (4) Sterilization and leak detection: sterilize in a water bath at 121°C for 15 minutes;

[0066] (5) The sterilized products that have passed the test will be inspected and packaged.

[0067] Performance Test:

[0068] The ambroxol hydrochloride content, pH value, related substances, osmotic pressure molar concentration and dissolution time in the ambroxol hydrochloride injection obtained in Examples 1 to 3 were investigated.

[0069] Among them, the test method is as follows:

[0070] The method for determining the content of ambroxol hydrochloride shall be carried out in accordance with the "High Performance Liquid Chromatography Operating Procedure" (SOP10aJ024).

[0071] The pH value was determined according to the pH Determination Operating Procedure (SOP10aJ020).

[0072] The determination method of relevant substances shall be carried out in accordance with the "High Performance Liquid Chromatography Operating Procedure" (SOP10aJ024).

[0073] To determine the osmotic pressure molar concentration, take an appropriate amount of this product and determine it according to the "Standard Operating Procedure for Determination of Osmotic Pressure Molar Concentration" (SOP10aJ025).

[0074] Dissolution time refers to the time from the time when ambroxol hydrochloride is added into water to the time when it is completely dissolved.

[0075] The test results are compared as follows:

[0076] Table 4. Test results

[0077]

[0078] Comparison of test results: According to the test results in the table, the content, osmotic pressure molar concentration, pH value, and related substances in the three schemes all meet the pharmacopoeia standards. The addition of citric acid and anhydrous disodium hydrogen phosphate in Scheme 1 has a faster dissolution time, saves costs, and also ensures the safety of medication. At the same time, the comparison of the three schemes makes it easier to purchase in the selection of CDE raw and auxiliary packages, and multiple manufacturers can be selected. Therefore, the prescription in the present invention is more suitable for commercial production in workshops.

[0079] Table 5. Long-term data of Example 1

[0080]

[0081]

[0082] Table 6. Accelerated test data of Example 1

[0083]

[0084] Table 7. High temperature test of Example 1

[0085]

[0086] Table 8. Lighting test of Example 1

[0087]

[0088]

[0089] Table 9. Low temperature test of Example 1

[0090]

[0091] Table 10. Freeze-thaw test of Example 1

[0092]

[0093]

[0094] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example.

[0095] Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. A method for preparing ambroxol hydrochloride injection, characterized in that, The steps include: (1) Add 60% to 90% of the prepared amount of water for injection into the liquid preparation tank, control the temperature of the water for injection to 60°C to 80°C, stir, add a pH adjuster, stir to dissolve, add 15g of ambroxol hydrochloride, stir to dissolve, add 15g of sodium chloride, stir to dissolve, add the remaining amount of water for injection, and obtain a liquid with a pH value of 4.5 to 5.5; (2) filtering the drug solution through a 0.22 μm polyethersulfone filter; (3) controlling the temperature of the liquid medicine to 20°C to 40°C, filling with nitrogen, and sealing by melting; (4) sterilizing the sealed drug solution at 115-125° C. for 10-20 min; (5) Light inspection and packaging.

2. The preparation method of ambroxol hydrochloride injection according to claim 1, characterized in that, The pH adjuster includes citric acid monohydrate and polyethylene glycol 400.

3. The preparation method of ambroxol hydrochloride injection according to claim 1, characterized in that, The pH adjusters include acids and salts.

4. The preparation method of ambroxol hydrochloride injection according to claim 3, characterized in that, The pH adjuster includes citric acid and anhydrous disodium hydrogen phosphate.

5. The method for preparing ambroxol hydrochloride injection according to claim 3, characterized in that, The pH adjuster includes citric acid monohydrate and disodium hydrogen phosphate dihydrate.

6. The method for preparing ambroxol hydrochloride injection according to claim 1, wherein The liquid preparation tank is a stainless steel tank.

7. The preparation method of ambroxol hydrochloride injection according to claim 1, characterized in that, The liquid dispensing tank comprises: Tank; and a weighing module, wherein the weighing module is arranged at the bottom of the tank body to display the weight of the weighing part.

8. The preparation method of ambroxol hydrochloride injection according to claim 1, characterized in that, The top of the tank body is formed with: a first feeding port, a second feeding port and an exhaust hole.

9. The preparation method of ambroxol hydrochloride injection according to claim 1, characterized in that, The packaging adopts brown borosilicate glass ampoule.

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